Skip to main content

Advertisement

SpringerLink
Log in

Treatment with hydrogen sulfide attenuates sublesional skeletal deterioration following motor complete spinal cord injury in rats

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Treatment with hydrogen sulfide mitigates spinal cord injury-induced sublesional bone loss, possibly through abating oxidative stress, suppressing MMP activity, and activating Wnt/β-catenin signaling.

Introduction

Spinal cord injury (SCI)-induced sublesional bone loss represents the most severe osteoporosis and is resistant to available treatments to data. The present study was undertaken to explore the therapeutic potential of hydrogen sulfide (H2S) against osteoporosis in a rodent model of motor complete SCI.

Methods

SCI was generated by surgical transaction of the cord at the T3–T4 levels in rats. Treatment with NaHS was initiated through intraperitoneal injection of 0.1 ml/kg/day of 0.28 mol/l NaHS from 12 h following the surgery and over 14 subsequent days.

Results

H2S levels in plasma of SCI rats were lower, which was restored by treatment with exogenous H2S. Treatment of SCI rats with exogenous H2S had no significant effect on body mass but increased bone mineral density in femurs and tibiae, increased BV/TV, Tb.Th, and Tb.N and reduced Tb.Sp in proximal tibiae, and increased mineral apposition rate (MAR), bone formation rate (BFR), and osteoblast surface and reduced eroded surface and osteoclast surface in proximal tibiae. More importantly, H2S treatment led to a significant enhancement in ultimate load, stiffness, and energy to max force of femoral diaphysis. Treatment of SCI rats with exogenous H2S reduced malondialdehyde (MDA) levels in serum and femurs, decreased hydroxyproline levels, suppressed activities of matrix metallopeptidase 9 (MMP9), and upregulated Wnt3a, Wnt6, Wnt10, and ctnnb1 expression in femurs.

Conclusion

Treatment with H2S mitigates SCI-induced sublesional bone loss, possibly through abating oxidative stress, suppressing MMP activity, and activating Wnt/β-catenin signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Gifre L, Vidal J, Carrasco J, Filella X, Ruiz-Gaspà S, Muxi A, Portell E, Monegal A, Guañabens N, Peris P (2015) Effect of recent spinal cord injury on wnt signaling antagonists (sclerostin and Dkk-1) and their relationship with bone loss. A 12-month prospective study. J Bone Miner Res 30:1014–1021

    Article  CAS  PubMed  Google Scholar 

  2. Gifre L, Vidal J, Carrasco J, Portell E, Puig J, Monegal A, Guañabens N, Peris P (2014) Incidence of skeletal fractures after traumatic spinal cord injury: a 10-year follow-up study. Clin Rehabil 28:361–369

    Article  PubMed  Google Scholar 

  3. Roberts D, Lee W, Cuneo RC, Wittmann J, Ward G, Flatman R, McWhinney B, Hickman PE (1998) Longitudinal study of bone turnover after acute spinal cord injury. J Clin Endocrinol Metab 83:415–422

    CAS  PubMed  Google Scholar 

  4. Warden SJ, KBennell KL, Matthews B, Brown DJ, McMeeken JM, Wark JD (2002) Quantitative ultrasound assessment of acute bone loss following spinal cord injury: a longitudinal pilot study. Osteoporos Int 13:586–592

    Article  CAS  PubMed  Google Scholar 

  5. Vico L, Collet P, Guignandon A, Lafage-Proust MH, Thomas T, Rehaillia M, Alexandre C (2000) Effects of long-term microgravity exposure on cancellous and cortical weight-bearing bones of cosmonauts. Lancet 355:1607–1611

    Article  CAS  PubMed  Google Scholar 

  6. Leblanc AD, Schneider VS, Evans HJ, Engelbretson DA, Krebs JM (1990) Bone mineral loss and recovery after 17 weeks of bed rest. J Bone Miner Res 5:843–850

    Article  CAS  PubMed  Google Scholar 

  7. Recker R, Lappe J, Davies K, Heaney R (2000) Characterization of perimenopausal bone loss: a prospective study. J Bone Miner Res 15:1965–1973

    Article  CAS  PubMed  Google Scholar 

  8. Varzi D, Coupaud SA, Purcell M, Allan DB, Gregory JS, Barr RJ (2015) Bone morphology of the femur and tibia captured by statistical shape modelling predicts rapid bone loss in acute spinal cord injury patients. Bone 81:495–501

    Article  PubMed  Google Scholar 

  9. Minaire P, Berard E, Meunier PJ, Edouard C, Goedert G, Pilonchery G (1981) Effects of disodium dichloromethylene diphosphonate on bone loss in paraplegic patients. J Clin Invest 68:1086–1092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bryson JE, Gourlay ML (2009) Bisphosphonate use in acute and chronic spinal cord injury: a systematic review. J Spinal Cord Med 32:215–225

    Article  PubMed  PubMed Central  Google Scholar 

  11. Chang KV, Hung CY, Chen WS, Lai MS, Chien KL, Han DS (2013) Effectiveness of bisphosphonate analogues and functional electrical stimulation on attenuating post-injury osteoporosis in spinal cord injury patients-a systematic review and meta-analysis. PLoS One 8:e81124

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bauman WA, Cirnigliaro CM, La Fountaine MF, Martinez L, Kirshblum SC, Spungen AM (2015) Zoledronic acid administration failed to prevent bone loss at the knee in persons with acute spinal cord injury: an observational cohort study. J Bone Miner Metab 33:410–421

    Article  CAS  PubMed  Google Scholar 

  13. Wang R (2003) The gasotransmitter role of hydrogen sulfide. Antioxid Redox Signal 5:493–501

    Article  PubMed  Google Scholar 

  14. Wang R (2002) Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 16:1792–1798

    Article  CAS  PubMed  Google Scholar 

  15. Kesherwani V, Nelson KS, Agrawal SK (2013) Effect of sodium hydrosulphide after acute compression injury of spinal cord. Brain Res 1527:222–229

    Article  CAS  PubMed  Google Scholar 

  16. Campolo M, Esposito E, Ahmad A, Di Paola R, Wallace JL, Cuzzocrea S (2013) A hydrogen sulfide-releasing cyclooxygenase inhibitor markedly accelerates recovery from experimental spinal cord injury. FASEB J 27:4489–4499

    Article  CAS  PubMed  Google Scholar 

  17. Grassi F, Malik Tyagi A, Calvert JW, Gambari L, Walker LD, Yu M, Robinson J, Li JY, Lisignoli G, Vaccaro C, Adams J, Pacifici R (2015) Hydrogen Sulfide Is a Novel Regulator of Bone Formation Implicated in the Bone Loss Induced by Estrogen Deficiency. J Bone Miner Res (in press)

  18. Liu Y, Yang R, Liu X, Zhou Y, Qu C, Kikuiri T, Wang S, Zandi E, Du J, Ambudkar IS, Shi S (2014) Hydrogen sulfide maintains mesenchymal stem cell function and bone homeostasis via regulation of Ca(2+) channel sulfhydration. Cell Stem Cell 15:66–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Qin W, Li X, Peng Y, Harlow LM, Ren Y, Wu Y, Li J, Qin Y, Sun J, Zheng S, Brown T, Feng JQ, Ke HZ, Bauman WA, Cardozo CC (2015) Sclerostin antibody preserves the morphology and structure of osteocytes and blocks the severe skeletal deterioration after motor-complete spinal cord injury in rats. J Bone Miner Res 30:1994–2004

    Article  CAS  PubMed  Google Scholar 

  20. Sun L, Pan J, Peng Y, Wu Y, Li J, Liu X, Qin Y, Bauman WA, Cardozo C, Zaidi M, Qin W (2013) Anabolic steroids reduce spinal cord injury-related bone loss in rats associated with increased wnt signaling. J Spinal Cord Med 36:616–622

    Article  PubMed  PubMed Central  Google Scholar 

  21. Luo ZL, Tang LJ, Wang T, Dai RW, Ren JD, Cheng L, Xiang K, Tian FZ (2014) Effects of treatment with hydrogen sulfide on methionine-choline deficient diet-induced non-alcoholic steatohepatitis in rats. J Gastroenterol Hepatol 29:215–222

    Article  CAS  PubMed  Google Scholar 

  22. Zeng J, Lin X, Fan H, Li C (2013) Hydrogen sulfide attenuates the inflammatory response in a mouse burn injury model. Mol Med Rep 8:1204–1208

    CAS  PubMed  Google Scholar 

  23. Yang X, He B, Liu P, Yan L, Yang M, Li D (2015) Treatment with curcumin alleviates sublesional bone loss following spinal cord injury in rats. Eur J Pharmacol 765:209–216

    Article  CAS  PubMed  Google Scholar 

  24. Wang HD, Shi YM, Li L, Guo JD, Zhang YP, Hou SX (2013) Treatment with resveratrol attenuates sublesional bone loss in spinal cord-injured rats. Br J Pharmacol 170:796–806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310

    Article  CAS  PubMed  Google Scholar 

  26. Podenphant J, Larsen NE, Christiansen C (1984) An easy and reliable method for determination of urinary hydroxyproline. Clin Chim Acta 142:145–148

    Article  CAS  PubMed  Google Scholar 

  27. Vacek TP, Qipshidze N, Tyagi SC (2013) Hydrogen sulfide and sodium nitroprusside compete to activate/deactivate MMPs in bone tissue homogenates. Vasc Health Risk Manag 9:117–123

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Reiter AL, Volk A, Vollmar J, Fromm B, Gerner HJ (2007) Changes of basic bone turnover parameters in short-term and long-term patients with spinal cord injury. Eur Spine J 16:771–776

    Article  PubMed  Google Scholar 

  29. Lin T, Tong W, Chandra A, Hsu SY, Jia H, Zhu J, Tseng WJ, Levine MA, Zhang Y, Yan SG, Liu XS, Sun D, Young W, Qin L (2015) A comprehensive study of long-term skeletal changes after spinal cord injury in adult rats. Bone Res 3:15028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. d’Emmanuele diVilla Bianca R. Mitidieri E, Donnarumma E, Tramontano T, Brancaleone V, Cirino G, Bucci M, Sorrentino R (2015) Hydrogen sulfide is involved in dexamethasone-induced hypertension in rat. Nitric Oxide 46:80–86.

  31. Morimoto E, Li M, Khalid AB, Krum SA, Chimge NO, Frenkel B (2016) Glucocorticoids hijack Runx2 to stimulate Wif1 for suppression of osteoblast growth and differentiation. J Cell Physiol (in press)

  32. Yang M, Huang Y, Chen J, Chen YL, Ma JJ, Shi PH (2014) Activation of AMPK participates hydrogen sulfide-induced cyto-protective effect against dexamethasone in osteoblastic MC3T3-E1 cells. Biochem Biophys Res Commun 454:42–47

    Article  CAS  PubMed  Google Scholar 

  33. Maimoun L, Couret I, Micallef JP, Peruchon E, Mariano-Goulart D, Rossi M, Leroux JL, Ohanna F (2002) Use of bone biochemical markers with dual-energy x-ray absorptiometry for early determination of bone loss in persons with spinal cord injury. Metabolism 51:958–963

    Article  CAS  PubMed  Google Scholar 

  34. Itou T, Maldonado N, Yamada I, Goettsch C, Matsumoto J, Aikawa M, Singh S, Aikawa E (2014) Cystathionine γ-lyase accelerates osteoclast differentiation: identification of a novel regulator of osteoclastogenesis by proteomic analysis. Arterioscler Thromb Vasc Biol 34:626–634

    Article  CAS  PubMed  Google Scholar 

  35. Gambari L, Lisignoli G, Cattini L, Manferdini C, Facchini A, Grassi F (2014) Sodium hydrosulfide inhibits the differentiation of osteoclast progenitor cells via NRF2-dependent mechanism. Pharmacol Res 87:99–112

    Article  CAS  PubMed  Google Scholar 

  36. Callaway DA, Jiang JX (2015) Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases. J Bone Miner Metab 33:359–370

    Article  CAS  PubMed  Google Scholar 

  37. Jia Z, Zhu H, Li J, Wang X, Misra H, Li Y (2012) Oxidative stress in spinal cord injury and antioxidant-based intervention. Spinal Cord 50:264–274

    Article  CAS  PubMed  Google Scholar 

  38. Xu ZS, Wang XY, Xiao DM, Hu LF, Lu M, Wu ZY, Bian JS (2011) Hydrogen sulfide protects MC3T3-E1 osteoblastic cells against H2O2-induced oxidative damage-implications for the treatment of osteoporosis. Free Radic Biol Med 50:1314–1323

    Article  CAS  PubMed  Google Scholar 

  39. Williams S, Barnes J, Wakisaka A, Ogasa H, Liang CT (1999) Treatment of osteoporosis with MMP inhibitors. Ann N Y Acad Sci 878:191–200

    Article  CAS  PubMed  Google Scholar 

  40. Siwik DA, Pagano PJ, Colucci WS (2001) Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 280:C53–C60

    CAS  PubMed  Google Scholar 

  41. Rodda SJ, McMahon AP (2006) Distinct roles for hedgehog and canonical wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 133:3231–3244

    Article  CAS  PubMed  Google Scholar 

  42. Glass DA 2nd, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, Taketo MM, Long F, McMahon AP, Lang RA, Karsenty G (2005) Canonical wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764

    Article  CAS  PubMed  Google Scholar 

  43. Beggs LA, Ye F, Ghosh P, Beck DT, Conover CF, Balaez A, Miller JR, Phillips EG, Zheng N, Williams AA, Aguirre JI, Wronski TJ, Bose PK, Borst SE, Yarrow JF (2015) Sclerostin inhibition prevents spinal cord injury-induced cancellous bone loss. J Bone Miner Res 30:681–689

    Article  CAS  PubMed  Google Scholar 

  44. Fan K, Li N, Qi J, Yin P, Zhao C, Wang L, Li Z, Zha X (2014) Wnt/β-catenin signaling induces the transcription of cystathionine-γ-lyase, a stimulator of tumor in colon cancer. Cell Signal 26:2801–2808

    Article  CAS  PubMed  Google Scholar 

  45. Si YF, Wang J, Guan J, Zhou L, Sheng Y, Zhao J (2013) Treatment with hydrogen sulfide alleviates streptozotocin-induced diabetic retinopathy in rats. Br J Pharmacol 169:619–631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li N, Wang MJ, Jin S, Bai YD, Hou CL, Ma FF, Li XH, Zhu YC (2016) The H2S donor NaHS changes the expression pattern of H2S-producing enzymes after myocardial infarction. Oxidative Med Cell Longev 2016:6492469

    Google Scholar 

  47. Ahmad A, Sattar MA, Rathore HA, Abdulla MH, Khan SA, Azam M, Abdullah NA, Johns EJ (2016) Up regulation of cystathione γ lyase and hydrogen Sulphide in the myocardium inhibits the progression of isoproterenol-caffeine induced left ventricular hypertrophy in Wistar Kyoto rats. PLoS One 11:e0150137

    Article  PubMed  PubMed Central  Google Scholar 

  48. Jiang SD, Dai LY, Jiang LS (2006) Osteoporosis after spinal cord injury. Osteoporos Int 17:180–192

    Article  PubMed  Google Scholar 

  49. Yang M, Huang Y, Chen J, Chen YL, Ma JJ, Shi PH (2007) Activation of AMPK participates hydrogen sulfide-induced cyto-protective effect against dexamethasone in osteoblastic MC3T3-E1 cells. Biochem Biophys Res Commun 454:42–47

    Article  Google Scholar 

  50. Jain SK, Manna P, Micinski D, Lieblong BJ, Kahlon G, Morehead L, Hoeldtke R, Bass PF 3rd, Levine SN (2013) In African American type 2 diabetic patients, is vitamin D deficiency associated with lower blood levels of hydrogen sulfide and cyclic adenosine monophosphate, and elevated oxidative stress? Antioxid Redox Signal 18:1154–1158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong University College of Medicine, Youyi East Road 555, Xi’an, 710054, China

    X. Yang, D. Hao, M. Yang & B. He

  2. Diagnostic Center, Hong Hui Hospital, Xi’an Jiaotong University College of Medicine, Xi’an, 710054, China

    H. Zhang & B. Liu

Authors
  1. X. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B. He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. He.

Ethics declarations

Conflicts of interest

None.

Electronic supplementary material

ESM 1

(DOC 49 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, X., Hao, D., Zhang, H. et al. Treatment with hydrogen sulfide attenuates sublesional skeletal deterioration following motor complete spinal cord injury in rats. Osteoporos Int 28, 687–695 (2017). https://doi.org/10.1007/s00198-016-3756-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-016-3756-7

Keywords

Search

Navigation